scholarly journals Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo

2012 ◽  
Vol 209 (12) ◽  
pp. 2157-2163 ◽  
Author(s):  
Yan Zheng ◽  
Yuanyuan Zha ◽  
Gregory Driessens ◽  
Frederick Locke ◽  
Thomas F. Gajewski
Keyword(s):  
T Cell ◽  
Growth Response ◽  
Transcriptional Regulator ◽  
Early Growth ◽  
Response Gene ◽  
Early Growth Response ◽  
T Cell Anergy ◽  
Early Growth Response Gene ◽  
Cell Anergy

T cell receptor engagement in the absence of costimulation results in a hyporesponsive state termed anergy. Understanding the transcriptional regulation of other T cell differentiation states has provided critical information regarding the biology of T cell regulation in vivo. However, the transcriptional regulation of T cell anergy has been poorly understood. Using the key anergy target gene diacylglycerol kinase (DGK) α as a focal point, we identified early growth response gene 2 (Egr2) as a central transcription factor that regulates the anergic state. Conditional Egr2 deletion in peripheral T cells abolishes induced expression of DGK-α and other anergy genes and restores Ras/MAPK signaling, IL-2 production, and proliferation upon attempted anergy induction. Using superantigen- and tumor-induced anergy models, we found that Egr2 is necessary for anergy induction in vivo. Collectively, our results implicate Egr2 as an essential transcriptional regulator of the T cell anergy program.

scholarly journals Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease

2008 ◽  
Vol 205 (10) ◽  
pp. 2295-2307 ◽  
Author(s):  
Bo Zhu ◽  
Alistair L.J. Symonds ◽  
Joanne E. Martin ◽  
Dimitris Kioussis ◽  
David C. Wraith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Growth Response ◽  
Late Onset ◽  
Early Growth ◽  
Response Gene ◽  
Early Growth Response ◽  
Early Growth Response Gene ◽  
Ifn Γ

Maintaining tolerance of T cells to self-antigens is essential to avoid autoimmune disease. How self-reactive T cells are kept functionally inactive is, however, unknown. In this study, we show that early growth response gene 2 (Egr-2), a zinc-finger transcription factor, is expressed in CD44high T cells and controls their proliferation and activation. In the absence of Egr-2, CD44high, but not CD44low T cells, are hyperreactive and hyperproliferative in vivo. The accumulation of activated CD4+CD44high T cells leads to the development of a late onset lupuslike autoimmune disease characterized by the accumulation of interferon (IFN)-γ and interleukin (IL)-17–producing CD4+ T cells, loss of tolerance to nuclear antigens, massive infiltration of T cells into multiple organs and glomerulonephritis. We found that the expression of cyclin-dependent kinase inhibitor p21cip1 was impaired in Egr-2–deficient T cells, whereas the expression of IFN-γ and IL-17 in response to T cell receptor ligation was significantly increased, suggesting that Egr-2 activates the expression of genes involved in the negative regulation of T cell proliferation and inflammation. These results demonstrate that Egr-2 is an intrinsic regulator of effector T cells and controls the expansion of self-reactive T cells and development of autoimmune disease.

scholarly journals Early Growth Response Gene 1–mediated Apoptosis Is Essential for Transforming Growth Factor β1–induced Pulmonary Fibrosis

2004 ◽  
Vol 200 (3) ◽  
pp. 377-389 ◽  
Author(s):  
Chun Geun Lee ◽  
Soo Jung Cho ◽  
Min Jong Kang ◽  
Svetlana P. Chapoval ◽  
Patty J. Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Response ◽  
Transforming Growth Factor ◽  
Early Growth ◽  
Transient Wave ◽  
Response Gene ◽  
Early Growth Response ◽  
Early Growth Response Gene ◽  
Tgf Β1

Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-β1 has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-β1 in the lung and its roles in the pathogenesis of these responses are not completely understood. In addition, the relationships between apoptosis and other TGF-β1–induced responses have not been defined. To address these issues, we targeted bioactive TGF-β1 to the murine lung using a novel externally regulatable, triple transgenic system. TGF-β1 produced a transient wave of epithelial apoptosis that was followed by mononuclear-rich inflammation, tissue fibrosis, myofibroblast and myocyte hyperplasia, and septal rupture with honeycombing. Studies of these mice highlighted the reversibility of this fibrotic response. They also demonstrated that a null mutation of early growth response gene (Egr)-1 or caspase inhibition blocked TGF-β1–induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-β1–induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-β1 in vivo and define the critical role of Egr-1 in the TGF-β1 phenotype. They also demonstrate that Egr-1–mediated apoptosis is a prerequisite for TGF-β1–induced fibrosis and remodeling.

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